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001044114 1001_ $$0P:(DE-Juel1)176659$$aBorghans, Bart$$b0$$ufzj
001044114 245__ $$aAllosteric modulation of proton binding confers Cl- activation and glutamate selectivity to vesicular glutamate transporters
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001044114 520__ $$aVesicular glutamate transporters (VGLUTs) fill synaptic vesicles with glutamate andremove luminal Cl- via an additional anion channel mode. Both of these transportfunctions are stimulated by luminal acidification, luminal-positive membrane potential,and luminal Cl-. We studied VGLUT1 transporter/channel activation using acombination of heterologous expression, cellular electrophysiology, fast solutionexchange, and mathematical modeling. Cl- channel gating can be described with akinetic scheme that includes two protonation sites and distinct opening, closing, andCl--binding rates for each protonation state. Cl- binding promotes channel openingby modifying the pKa values of the protonation sites and rates of pore opening andclosure. VGLUT1 transports glutamate and aspartate at distinct stoichiometries:H+-glutamate exchange at 1:1 stoichiometry and aspartate uniport. Neurotransmittertransport with variable stoichiometry can be described with an alternating accessmodel that assumes that transporters without substrate translocate in the doubly protonatedstate to the inward-facing conformation and return with the bound amino acidsubstrate as either singly or doubly protonated. Glutamate, but not aspartate, promotesthe release of one proton from inward-facing VGLUT1, resulting in preferentialH+-coupled glutamate exchange. Cl- stimulates glutamate transport by making theglutamate-binding site accessible to cytoplasmic glutamate and by facilitating transitionsto the inward-facing conformation after outward substrate release. We concludethat allosteric modification of transporter protonation by Cl- is crucial for both VGLUT1transport functions.
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001044114 536__ $$0G:(GEPRIS)394431587$$aDFG project G:(GEPRIS)394431587 - FOR 2795: Synapsen unter Stress: akute Veränderungen durch mangelnde Energiezufuhr an glutamatergen Synapsen (394431587)$$c394431587$$x3
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001044114 7001_ $$0P:(DE-Juel1)157846$$aKortzak, Daniel$$b1
001044114 7001_ $$0P:(DE-Juel1)174421$$aLongo, Piersilvio$$b2$$ufzj
001044114 7001_ $$0P:(DE-Juel1)169471$$aKolen, Bettina$$b3
001044114 7001_ $$0P:(DE-Juel1)156429$$aMachtens, Jan-Philipp$$b4$$ufzj
001044114 7001_ $$0P:(DE-Juel1)136837$$aFahlke, Christoph$$b5$$eCorresponding author
001044114 773__ $$0PERI:(DE-600)2193340-6$$a10.1371/journal.pcbi.1013214$$gVol. 21, no. 6, p. e1013214 -$$n6$$pe1013214 -$$tPLoS Computational Biology$$v21$$x1553-734X$$y2025
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